Over the last decade, major advances have been made in the understanding of the biology of the mammalian tachykinin neuropeptides. It is now well established that substance-P (1), neurokinin A (NKA) (2), and neurokinin B (NKB) (3), all of which share a common C-terminal sequence Phe-X-Gly-Leu-Met-NH.sub.2, (Nakanishi S, Physiol Rev 1987;67:117), are widely distributed throughout the periphery and central nervous system (CNS) where they appear to interact with at least three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3, (Guard S, et al., Neurosci Int 1991;18:149). Substance-P displays highest affinity for NK.sub.1 receptors, whereas NKA and NKB bind preferentially to NK.sub.2 and NK.sub.3 receptors, respectively. Recently, all three receptors have been cloned and sequenced and shown to be members of the G-protein-linked "super family" of receptors (Nakanishi S, Annu Rev Neurosci 1991;14:123). A wealth of evidence supports the involvement of tachykinin neuropeptides in a variety of biological activities including pain transmission, vasodilation, smooth muscle contraction, bronchoconstriction, activation of the immune system (inflammatory pain), and neurogenic inflammation (Pernow B, Pharmacol Rev 1983;35:85). However, to date, a detailed understanding of the physiological roles of tachykinin neuropeptides has been severely hampered by a lack of selective, high affinity, metabolically stable tachykinin receptor antagonists that possess both good bioavailability and CNS penetration. Although several tachykinin receptor antagonists have been described (Tomczuk B E, et al., Current Opinions in Therapeutic Patents 1991;1:197), most have been developed through the modification and/or deletion of one or more of the amino acids that comprise the endogenous mammalian tachykinins such that the resulting molecules are still peptides that possess poor pharmacokinetic properties and limited in vivo activities.
However, since 1991, a number of high-affinity nonpeptide antagonists have been reported. Snider R M, et al, (Science 1991;251:435), and Garret C, et al, (Proc Natl Acad Sci 1991;88:10208), described CP-96,345 and RP 67580, respectively, as antagonists at the NK.sub.1 receptor, while Advenier C, et al., (Brit J Pharmacol 1992;105:78), presented data on SR 48969 showing its high affinity and selectivity for NK.sub.2 receptors. It is of interest that most of the nonpeptide tachykinin receptor antagonists described to date arose, either directly or indirectly, out of the screening of large compound collections using a robust radioligand binding assay as the primary screen. Recently, FK 888, a "dipeptide" with high affinity for the NK.sub.1 receptor was described (Fujii J, et al., Neuropeptide 1992;22:24).
International Publication Numbers WO 93/01169, WO 93/01165, and WO 93/001160 cover certain nonpeptide tachykinin receptor antagonists.
Substance-P is widely distributed throughout the periphery and central nervous system. It is believed to mediate a variety of biological actions, via an interaction with three receptor types referred to as NK.sub.1, NK.sub.2, and NK.sub.3, including smooth muscle contraction, pain transmission, neuronal excitation, secretion of saliva, angiogenesis, broncho-constriction, activation of the immune system and neurogenic inflammation.
Accordingly, compounds capable of antagonizing the effects of substance-P at NK.sub.1 receptors will be useful in treating or preventing a variety of brain disorders including pain, anxiety, panic, depression, schizophrenia, neuralgia, and addiction disorders; inflammatory diseases such as arthritis, asthma, and psoriasis; gastrointestinal disorders including colitis, Crohn's disease, irritable bowel syndrome, and satiety; allergic responses such as eczema and rhinitis; vascular disorders such as angina and migraine; neuropathological disorders including Parkinson's disease, multiple sclerosis, and Alzheimer's disease; and ophthalmic diseases including scleroderma.
The compounds of the invention, NK.sub.1 receptor antagonists, are useful as anti-angiogenic agents for the treatment of conditions associated with aberrant neovascularization such as rheumatoid arthritis, atherosclerosis, and tumor cell growth. They will also be useful as agents for imaging NK.sub.1 receptors in vivo in conditions such as ulcerative colitis and Crohn's disease.